Molecular and physiological studies have revealed that inflammation of adipose tissue is a key determinant in the development of the metabolic syndrome and a variety of animal models have been utilized to identify mechanisms that link adipocytes and macrophages to disease. Of these, the Fatty Acid Binding Protein 4 (FABP4, also known as aP2) loss/gain mouse has been particularly insightful in developing our current understanding of inflammation, ER stress, mitochondrial dysfunction and metabolic disease. Fatty acid binding proteins are intracellular FFA chaperones found expressed at high levels in adipocytes and macrophages. Surprisingly, when placed on high fat diets, FABP4 knockout mice exhibit attenuated characteristics of the metabolic syndrome including diminished lipolysis, reduced TNF? and increased adiponectin expression, improved insulin sensitivity, decreased NF-?B activation, protection from asthma and diminished atherogenic capacity. In contrast, mice over-expressing FABP in adipose tissue exhibit potentiated characteristics of the metabolic syndrome including increased lipolysis, exacerbated insulin resistance, decreased adiponectin secretion, and mild cardiac hypertrophy. Similar to the animal models, humans with decreased adipocyte FABP (arising via a polymorphism in the FABP4/aP2 promoter) exhibit reduced risk for hypertriglyceridemia, type 2 diabetes and cardiovascular disease. During the last funding cycle the laboratory has identified a novel FABP4-UCP2 axis that regulates lipid metabolism in macrophages and adipocytes. Briefly, molecular, genetic or pharmacologic loss of FABP leads to increased cellular fatty acids and a cascade of events linked to PPAR? activation and the up regulation of UCP2. Increased expression of UCP2 enables increased ?-oxidation of FFA, attenuates pyruvate entry into the mitochondrion, reduces the level of reactive oxygen species and oxidative stress. Diminished ROS reduces mitochondrial protein oxidation, the mitochondrial Unfolded Protein Response (mtUPR), activation of NF-?B signaling, and induction of the inflammasome. The central hypothesis for this application is that the FABP4-FFA equilibrium controls activation of SirT1 and subsequently UCP2 expression in macrophages. Moreover, up regulation of UCP2 is both necessary and sufficient to shift immune cells of high fat fed mice from a classically activated pro-inflammatory M1 phenotype to the alternatively activated anti-inflammatory M2 form. To test this hypothesis, the following specific aims are proposed: Aim 1. Evaluate the regulation of SirT1 by fatty acids and its control by FABP4. Aim 2. Examine cellular metabolism and polarization of cultured macrophages stably overexpressing UCP2. Aim 3. Evaluate the metabolic effects of macrophage-specific knockout and overexpression of UCP2 in experimental mice.